Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor-receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist (3)H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in (3)H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists.

Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (WT; point-to-point communication via private channels, e.g. synaptic transmission) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid). Volume and synaptic transmission become integrated because their chemical signals activate different types of interacting receptors in heteroreceptor complexes located synaptically and extrasynaptically in the plasma membrane. In VT, we focus on the role of the extracellular-vesicle type of VT, and in WT, on the potential role of the tunnelling-nanotube (TNT) type of WT. The so-called exosomes appear to be the major vesicular carrier for intercellular communication but the larger microvesicles also participate. Extracellular vesicles are released from cultured cortical neurons and different types of glial cells and modulate the signalling of the neuronal-glial networks of the CNS. This type of VT has pathological relevance, and epigenetic mechanisms may participate in the modulation of extracellular-vesicle-mediated VT. Gerdes and co-workers proposed the existence of a novel type of WT based on TNTs, which are straight transcellular channels leading to the formation in vitro of syncytial cellular networks found also in neuronal and glial cultures.